The first GWAS performed in an HIV cohort identified a single nucleotide polymorphism (SNP) located 35Kb upstream of the HLA-C gene termed -35 that associated with control of HIV viral load. The -35 SNP also associated with surface expression levels of HLA-C. We subsequently identified a microRNA (miRNA) binding site in the 3untranslated region (3UTR) of HLA-C, which is polymorphic and explains the differential cell surface expression of HLA-C across the various allotypes. Variation in this binding site is in near perfect linkage disequilibrium with the -35 SNP. We showed definitively through multiple approaches that miR-148a binds strongly to a specific sequence that is present in the HLA-C 3UTR of low expression HLA-C alleles, which causes the low cell surface expression, but this miRNA binds poorly to the alternative form of that sequence which is present in the 3UTR of high expression alleles thus leaving the corresponding mRNA intact. We also showed that the variation in the miR-148a binding site associates strongly with HIV viral load control. We further demonstrated that the common ancestor of all extant HLA-C alleles was suppressed by miR-148a. Substitutions that prevent miR-148a binding arose by a sequence exchange event between an HLA-C allele and an HLA-B allele that occurred 3-5MYA, resulting in an HLA-C variant that escaped from miR-148a downregulation. In addition, we showed that selection played a role in the successful spread of the HLA-C escape alleles.The miR-148a gene region (MIR148A) is also polymorphic and has been shown to have remarkable selection signature in various populations across the world. miR-148a is involved in the regulation of molecular pathways related to cellular development, differentiation, proliferation, apoptosis, neuronal development, epigenetic control of gene expression and immune system. Data is accumulating to suggest deregulation of miR-148a expression is closely associated with a multitude of human diseases. Our preliminary data suggest that a variant in the MIR148A gene region associates with expression of miR-148a and also epistatically interacts with the variation in the miR-148a binding region of HLA-C 3UTR to control HIV viral replication. We propose that the polymorphisms in the MIR148A region modulate its expression and in turn affect cellular and immune pathways affecting host defense against pathogens and tumors. We are further characterizing the polymorphism(s) in the MIR148A region that modulate its expression and in turn affect downstream cellular and immune pathways involved in host defense against pathogens and tumors.The HLA-C07:01:01G allele group consists of three nonsynonymous alleles, C07:01:01, C07:06 and C07:18, plus C07:01:02, which is synonymous to C07:01:01. All of these alleles have identical exons 2, 3 and 4, but differ in exons 5 or 6. Therefore routine sequence-based typing (SBT) of exons 2 and 3 is unable to resolve these subtypes, resulting in ambiguous typing results in population and disease cohort studies. We fully characterized C07:01:01G subtypes in European and African Americans and examined their relative frequency distributions. In European Americans C07:01:01G is predominantly represented by C07:01:01 (94.4%), whereas C07:01:02 (1.1%) and C07:18 (4.5%) were detected relatively infrequently. In African Americans C07:18 (42.4%) showed a high frequency similar to that of C07:01:01 (44.7%) whereas C07:06 was detected at a low frequency (4.7%). C07:06 was found exclusively on B44:03 carrying haplotypes in both ethnic groups, but C07:18 showed multiple linkage relationships with HLA-B. These results demonstrate that C07:01:01G as defined by routine SBT is a heterogeneous group of alleles, especially among individuals of African origin. If indeed C07:01:01G subtypes confer functional differences, their characterization may provide further insights into the effect of HLA matching for clinical transplantation and HLA association with human disease.